(introductory text...)

J. Karlberg ¹, F. Jalil ², B. Lam ¹, L. Low ¹ and C.Y. Yeung ¹

1 Department of Paediatrics, Queen Mary Hospital, University of Hong Kong, Hong Kong and

² Department of Social and Preventive Paediatrics, King Edward Medical College, Lahore, Pakistan

1. Introduction

It is well documented that infants living in developing countries have mean birth lengths close to those reported from Western Europe and North America (WHO Working Group, 1986; Martorell & Habicht, 1986). However, between 4-6 months and 18 months of age the mean lengths' curves diverge, so that by 24 months the difference is considerable (WHO Working Group, 1986; Martorell & Habicht, 1986; Manwani & Agarwal, 1973; Mata, 1978; Karlberg, Jalil & Lindblad, 1988; Black et al., 1982; Jalil et al., 1989; Degan et al., 1983; Waterlow, Ashworth & Griffiths, 1980; Zumrawi, Dimond & Waterlow, 1987; Costello, 1989; Dewey et al., 1992). During the second and third year of life, the mean growth curve of infants in developing countries again almost parallels the Western standard curve. The reason for this faltering process is not exactly known, as it can be present in infants of normal or close to normal nutritional status (Degan et al., 1983). Plausible causative mechanisms, involving such factors as feeding patterns, general under-nutrition, specific nutrient deficits, disease, serum and intracellular growth factors, and psycho-social conditions, are discussed in other chapters of this supplement.

In this chapter we discuss the three phases of linear growth-infancy, childhood and puberty in relation to growth faltering in early life. The key process is the onset of the second phase of growth, the childhood phase, that normally takes place at 6 to 12 months of age. Illustrations are taken from two longitudinal studies carried out in Lahore, Pakistan, and Hong Kong.

2. The three phases of linear growth

2.1. Hormonal regulation of linear growth

The growth process is under the control of the endocrine system. However, not only hormones are involved; hormone-binding proteins, growth factors and their binding proteins, as well as the stage of maturity and quantity of the hormone and growth factor receptors on the target cells may play a critical role too (Cianfarani & Holly, 1989; Waters et al., 1990). Furthermore, the secretion of hormones, such as growth hormone (GH), follows a pulsatile pattern with higher peaks during the nights as well as during puberty (Stanhope, Pringle & Brook, 1988). Such growth regulatory mechanisms interact and change in character over the ages (Masse, de Zegter & Vanderschueren-Lodeweyckx, 1992). A further confusing element is that some growth can take place without involvement of central steering mechanisms, as illustrated by an animal study showing that catch-up growth was regulated locally, at the tissue level, and not necessarily by the influence of circulating serum growth factors (Baron et al., 1993). For these reasons, the measurement of a hormone or growth factor in a single serum, urine or tissue sample will shed light on only a small part of this very complicated puzzle.

It is generally agreed that we have at least three distinct endocrine phases of linear growth, as indicated by the solid upper curve in Fig. 1. The pattern of postnatal growth is well documented; a high growth rate is observed from fetal life, with a rapid deceleration up to about 3 years of age. This is followed by a period with lower, slowly decelerating velocity up to puberty. Puberty starts with an increased rate of growth, and after the age of peak height velocity has been reached a deceleration is noted until growth ceases.

Fig. 1. The ICP growth model for height for boys (Karlberg, 1989a). The mean functions are plotted for each of the three components as well as the combined growth. The average at onset of the childhood and puberty components were used. The interrupted curve at 3 years reflects the change in measuring position from lying to standing up (could have been given at 1 or 2 years, as well). The total gains given by each component are given in Table 1. The key hormones involved in the regulation of growth are also given.

How fetal linear growth is regulated is not precisely defined and no key circulating hormone has so far been identified (Gluckman, 1989; Milner & Hill, 1987; Hill, 1989). Uterus size, nutritional support and oxygen level in conjunction with insulin-like growth factors and insulin are believed to be involved in regulating fetal growth (Gluckman, 1989; Milner & Hill, 1987; Hill, 1989).

During fetal life the serum GH level is high, and GH receptors have also been detected (Hill et al., 1988; Werther, Haynes & Waters, 1991). Fetal linear growth, however, is known to be almost independent of GH (Gluckman, 1989; Milner & Hill, 1987). A lack of growth response to GH during fetal life may be due to immature GH-specific receptors in the growth plate, as noted in the rabbit (Barnard et al., 1988). GH-deficient children are on average 1-2 cm, or 2-4% shorter than normal infants at birth (Karlberg & Albertsson-Wikland, 1988; Albertsson-Wikland, Niklasson & Karlberg, 1990; Tse, Hindmarsh & Brook, 1989; Gluckman et al., 1992). Whether this minor deviation is a secondary effect due to the lack of the influential metabolic action of GH or to the lack of a direct effect of GH on the cartilage, is still a matter of debate.

It is more generally accepted that GH is responsible for growth during childhood provided that thyroid hormone secretion is normal. The exact age at which GH begins to control linear growth in humans is still uncertain (vice infra). The majority of children with isolated GH deficiency grow more or less normally during the first 6 months of life, but not thereafter (Karlberg & Albertsson-Wikland, 1988; Albertsson-Wikland, Niklasson & Karlberg, 1990; Tse, Hindmarsh & Brook, 1989; Gluckman et al., 1992).

Growth during adolescence is related both to GH and sex steroids - testosterone in males and oestrogens in females (Copeland, Paunier & Sizonenko; 1977; Keenan et al., 1993). Both GH and sex hormones are needed for normal pubertal growth, although the presence of only one of them is associated with some growth during this period. It is not clear whether GH and sex steroids interact or act independently of each other (Pescovitz, 1990).

It is thus reasonable to conclude that linear growth from birth to maturity is regulated by at least three different growth-promoting systems. Two simultaneously active, superimposed, systems are known to be involved in the adolescent growth spurt. Similarly, a postnatal continuation of the nutritionally driven fetal growth in conjunction with the GH-dependent phase of childhood growth characterizes the growth in the first year of life (Tse, Hindmarsh & Brook, 1989).

2.2. The infancy-childhood-puberty (ICP) growth model

The ICP growth model breaks down linear growth mathematically into three additive and partly superimposed components - infancy, childhood and puberty (Karlberg, 1987, 1989a,b; Karlberg et al., 1987a,b). Fig. 1 shows the shape, size and timing of each of the three components, together with their additive effects in boys.

The ICP model represents linear growth during the first three years of life by a combination of a sharply decelerating infancy component and a slowly decelerating childhood component, the latter acting from the second half of the first postnatal year. From about 3 years of age to maturity, linear growth is represented by the sum of the infancy and childhood components and a sigmoid shaped puberty component operating throughout adolescence (Fig. 1).

2.3. Curve fitting procedure

The ICP-model was sequentially fitted to the individual growth curves from birth to adulthood for the children included in the Swedish longitudinal study (Karlberg, 1987; 1989a). In view of the equilibrium of the growth process it seemed rational to represent the period of slowly decelerating growth from 3 years of age to the onset of puberty by a single component, which was called childhood phase. A simple quadratic function was found to fit growth during this period very well. After subtraction of the extrapolated values of the childhood component from the observed values during the periods before and after this phase, two additional components were extracted and modelled. As a result of this modelling process, three separate components could be isolated (Karlberg, 1987; 1989a).

1. Infancy: This constantly decelerating component begins before birth and tails off by 3-4 years of age. It can be represented by an exponential function:

(1)

2. Childhood: This phase begins during the first year of life at age t_C, decelerates slowly and advances until maturity at age t_E A simple second degree polynomial provides a sufficient model for this component:

(2)

3. Puberty: This phase depicts the additional growth induced by puberty and accelerates up to age at peak velocity (t_V). It then decelerates till growth finishes (t_E). It can be modelled using a logistic function:

(3)

In these functions, Y denotes attained body size for the relevant component at time t in years from birth and the a's, b's and c's are constants. Age at end of growth (t_E) was specified as the middle of the first one-year interval after age at peak velocity, when the overall gain was less than that in the childhood component alone.

2.4. Biological interpretation of the modelled components

Empirical observations have shown that the three components of the ICP model can be observed in isolation, and that they are additive (Karlberg et al., 1987a,b; Karlberg 1989a,b, 1990). Each component of this model is therefore assumed to represent a separate biological phase of the growth process (Karlberg, 1989a). The infancy component, tentatively starting in mid-gestation and continuing, with a rapidly decelerating influence, up to 3-4 years of age, is claimed to represent the postnatal continuation of fetal growth. It is assumed that the childhood component, slowly decelerating during childhood and adolescence, corresponds basically to the effect of GH. The sigmoid shaped puberty component, the size of which is found to be independent of its timing, most likely describes the part of adolescent linear growth stimulated by sex steroids.

In the following presentation we will focus primarily on the age at onset of the childhood phase of growth. In normal infants, the onset occurs between 6 and 12 months of age and is typically abrupt (Karlberg, 1987; 1989b; 1990; Karlberg et al., 1987a), as illustrated, for instance, by the growth of a Pakistani girl plotted out in Figs 2a-f. What mediates the onset of the childhood phase of growth has not been elucidated, because information about the serum level of growth factors, hormones, the serum globulins involvement and the hormone and growth factor receptor activity and their interaction is still lacking during this critical period. However, the most plausible explanation is that it represents the age at which GH begins to influence normal human linear growth significantly. There are two major observations supporting this idea. Firstly, most (84%) of the increased gain in total body length is localised in the lower segment of the body (Karlberg, 1990). It is known that the growth of the long bones, as represented in the legs, is more sensitive to GH than other bone structures, such as the short bones in the vertebra (Frasier, 1983). Secondly, in children with isolated GH deficiency who receive no hormonal therapy, this tempo change of early linear growth is completely absent (Karlberg & Albertson-Wikland, 1988; Tse, Hindmarsh & Brook, 1989). Some other empirical observations point in the same direction (Karlberg, 1990).

Fig. 2. Length and length velocity for a normal Pakistani belonging to an upper middle class family; the monthly recorded values have been used in (a), every second month values in (b), etc. The growth rate has been expressed in mm/month in all graphs.

Figure (2a)

Figure (2b)

Figure (2c)

Figure (2d)

Figure (2e)

Figure (2f)

The final adult height of an individual is the additive result of the three underlying components (Fig. 1). This graph gives the mean path of each component, but there is an individual variation around these mean values, and the SD values for each component are 2-4 cm. It is not only the magnitude of each component that is important for the final height, but also the duration of the childhood phase; a late onset reduces height, and a late end point increases height (Karlberg, 1989a).

Table 1 includes the mean total contribution of each component to height, sitting height and leg length for the two sexes of the Swedish study. The infancy component is contributing more to sitting height than the childhood component, whereas the opposite is true for leg length. Different body tissues are thus unequally influenced by each of the three phases of growth. There is also a sex difference in the influence of the three components; the sex difference in the infancy and puberty components is related to their magnitude, whereas the childhood sex difference is basically due to a disparity in duration (2 years longer in boys than in girls; Karlberg, 1989a).

3. Measuring and monitoring linear growth in early life

3.1. Growth rate estimates and interval lengths

Growth rates usually covary with factors that can affect health, such as socio-economic status, season, disease, intervention, feeding patterns, nutritional status, serum nutritional factors or serum growth factors. Growth rate measurements, however, also include measuring errors. Therefore, we have to select intervals for growth rate estimations that are both short enough to be related to the indicator under observation and long enough to be sure that measuring errors are of minor importance.

Early human linear growth is commonly measured in terms of total body length or lower leg length, the latter being measured by the modified knemometer for infants (Michaelson et al., 1991). Both measures include measuring errors, although knemometer data include much less technical error than measures of supine length or height (Michaelson et al., 1991; Valk et al., 1983; Hermanussen et al., 1988; Wales & Milner, 1987; Wit et al., 1987; Dean, Schentag & Winter, 1990). Both measures include soft tissues and not only the skeleton; changes in the thickness of the soft tissues over time will therefore influence growth rate calculations (Hermanussen et al., 1988). The minimum time interval for calculations of lower leg length growth rates has been set at one month (Michaelson et al., 1991; Wit et al., 1987). The reason for selecting this rather long interval is to avoid an increased variation in the growth rate measure; true differences between groups will be less easy to detect when the variation is large.

Table 1. Mean total gain in height, sitting height and leg length for each component of the ICP growth model. The effect on sitting height and height due to the change in measuring position at 3 years of age has been corrected in proportion to attained size at 3 years of age for the infancy and childhood components

Measure	Sex	Infancy component (cm)	Childhood component (cm)	Puberty component (cm)	Total (cm)
Sitting height	Boys	48.9	36.7	8.8	94.4
	Girls	48.0	34.7	5.9	88.5
Leg length	Boys	30.0	48.6	6.6	85.2
	Girls	28.8	43.7	5.0	77.5
Total height	Boys	79.0	85.2	15.4	179.6
	Girls	76.8	78.4	10.9	166.1

As far as we know, the minimum interval between supine length measurements has not yet been clearly defined, although some have recommended monthly intervals (WHO Working Group, 1986). Using very short intervals may produce growth rate patterns that are difficult to interpret. For instance, daily or weekly length measurements in early life seem to suggest a pulsatile or saltatory growth pattern (Lampl, Veldhuis & Johnson, 1992). Whether this pattern is true or just reflects measuring errors or soft tissue changes cannot be determined when using total body length. An experimental study of the daily increase in the growth plate of the rabbit did not show any saltatory growth pattern (Oerter et al., 1993).

Supine length is commonly used in linear growth studies in early life. In our research work we are interested in defining the age at onset of the childhood phase of growth, which can be determined mathematically or visually using the ICP-based growth charts (Karlberg, 1989b). The influence of the measurement interval on the determination of this stage of maturity of human growth is illustrated by the measurements of the supine length of a healthy Pakistani girl belonging to an upper middle class family (Figs 2a-f). The monthly values from birth to 36 months are plotted in Fig. 2a. Four monthly values were missing at 15 to 34 months of age, and linear interpolation was used to estimate them. The onset of the childhood phase of growth for this girl can be determined by observing either the length or the length velocity curve: the growth curve has an exponential shape till about 10 months of age, then it becomes more linear.

Figs 2b-f show the growth of the same infant at increasingly longer intervals of observation of 2,3, 4,5 and 6 months. In all these graphs the growth rate has been expressed uniformly, i.e. in units of mm change per month. Two conclusions can be reached: (i) that the age at onset of the childhood phase - at around 10 months in this girl - can be determined only when the interval between measurements is less than 3-4 months, and (ii) that the variation in growth rates over time is highly dependent on the length of the interval.

Fig. 3. Length velocity for the same girl as described in Fig. 2 using the six different age intervals. The growth rate values have been computed as the change over the interval without dividing for the length of the interval.

In Fig. 3, the six growth rate curves given in Figs 2a-f are all shown together. The growth rates are presented here as the observed change over the specific time interval. For knemometer measurements one has accepted that the technical error should be less than 10% of the measured growth rate (Michaelson et al., 1991; Wit et al., 1987). Applying this approach to supine length, assuming a small technical error of 0.2 cm, the growth rate over a certain interval should be over 2 cm; monthly intervals can be used till 5 months of life and two months' intervals at higher ages in infancy, based on the curves given in Fig. 3. For defining the onset of the childhood phase of growth, 3 months' intervals are currently being recommended (Karlberg et al., 1987a; Karlberg, 1989b); that should, in most situations, rule out any major influence of measuring errors.

3.2. Monitoring of linear growth in early life

During the period preceding the age of onset of the childhood component, 83% of normal infants have a non-linear decelerating growth pattern, free from seasonal influences (Karlberg et al., 1987a). For the majority of the infants this phase of growth seems to be very stable over time, although the magnitude of the infancy component varies from individual to individual.

At the age of onset of the childhood component, 76% of normal infants show an abrupt increase in growth rate (Karlberg et al., 1987a). A smooth pattern is more common in infants with an early onset of the childhood component than in those with a late onset; this is due to the decelerating influence of the infancy component. A smooth pattern may also reflect an onset halfway between two observations. Children with a small infancy component have an early onset of the childhood component, which seemingly compensates for the initial low gain. Girls have an earlier onset than boys, which coincides with the lower initial velocity of their infancy component. The onset of the childhood component is thus related to the magnitude of the infancy component. Onset of the childhood component after 12 months of age did not occur in a Swedish study of healthy children (Table 2) (Karlberg et al., 1987a). Later onset is indicative of disturbances in the growth process (Table 2) (Karlberg, Jalil & Lindblad, 1988; Albertsson-Wikland, Niklasson & Karlberg, 1990; Karlberg et al., 1988; 1991; Karlberg & Wit, 1991; Karlberg & Albertsson-Wikland, 1988; Karlberg et al., 1991; Karlberg, Hägglund & Strömquist, 1991; Karlberg, Kjellmer & Kristiansson, 1991).

About two-thirds of normal children shift centiles for linear growth during the first 18 months of life after which the influence of parental stature becomes more important (Smith, 1977). This phenomenon can be explained by a gradual shift in influence from the infancy to the childhood component during this period.

In the second year of life, growth is a result of both the infancy and childhood components. The majority (75%) of normal infants displays a fairly constant growth rate with a total gain close to average during this period (Karlberg et al., 1987a), while others are more variable in their growth pattern. This variation is found to be seasonal, and to be greater for those experiencing a late onset of the childhood component (Karlberg et al., 1987a). This indicates an initial irregular effect on this component, but the fluctuations in growth rate have no clear effect on the total observed gain during the second year of life. Seasonal variations and transient irregular effects of the childhood component may thus cause fluctuations, which will be reduced by calculating the growth rate over longer intervals.

4. Growth faltering in linear growth

4.1. The theory

Fig. 4 depicts the two phases of growth during the first three years of life; the supposedly nutrition-dependent infancy phase and the GH dependent childhood phase, as well as the sum of the two. The age at onset of the childhood component occurs at 6 to 12 months of age in normal Swedish children, but is delayed in groups of infants with growth related disorders (Table 2).

Table 2. Mean and SD, in months, for the age at onset of the childhood component of supine length for different populations. The proportions of the infants being delayed (>12 months) in the age at onset are also given

	Age at onset of the childhood phase
	Boys				Girls
	n	Mean mths	SD mths	% delayed	n	Mean mths	SD mths	% delayed
Normal Swedish infants a	111	8.86	1.96	0.0	80	8.13	1.92	0.0
Pakistani infants *b	169	13.90	3.94	74.0	133	13.85	4.43	73.9
Celiac disease *c	18	12.22	2.99	55.6	45	11.04	2.90	44.4
Turner syndrome *d					47	11.54	3.20	36.2
Cystic fibrosis **e	26	9.71	2.04	11.5	19	8.45	1.76	5.3
Sotos syndrome ***f	11	14.27	5.20	72.7	2	16.50	-	50.0
Congenital dislocation of the hip ****g	1	7.0	-	0.0	13	8.69	1.41	0.0

* Disturbed growth and delayed childhood onset.
** Disturbed growth, but close to normal childhood onset.
*** Excessive infancy growth and delayed childhood onset.
**** Normal growth, but immobilised at 6 to 14 months of age.
^a Karlberg et al., 1987a;
^b Karlberg, Jalil & Lindblad, 1988;
^c Karlberg et al., 1988
^d Karlberg et al., 1991
^e Karlberg Kjellmer & Kristiansson, 1991;
^f Karlberg & Wit, 1991;
^g Karlberg, Hägglund & Strömquist, 1991.

Fig. 4. The shape of the infancy and childhood phase at birth to 3 years of age. The infancy phase is taken to be nutrition driven and the childhood phase GH dependent. The age at onset of the latter phase occurs normally at 6 to 12 months of age (Table 2).

The significance of late onset of the childhood component in relation to attained height in subsequent years is depicted in Fig. 5 (Karlberg, 1989). The curves drawn are theoretical extrapolations, since the impact of late onset of the childhood component has been considered alone. The curves included represent the mean functions of the infancy and childhood components of the ICP growth model. The curves represent the path of length/height for different onset times of the childhood component. For instance, an onset at 24 months of age produces an attained height at 8 years of age of 2 SD below the mean.

A delay in the onset of the childhood phase results in a faltering pattern in length, which is similar to the faltering pattern in growth between 6 and 18 months seen in infants in developing countries. The following sections give some empirical support to this theory.

Fig. 5. Illustration of the effect of late onset of the childhood phase assuming normal action of the infancy component (dotted lines). This is contrasted with the path of an average normal child (solid line) with onset at 9 months of age. Mean and 1 to 6 SD below the mean of attained height at 8 years of age are all indicated (solid lines to the right) (Karlberg 1989).

4.2 Observational studies of growth faltering - Lahore, Pakistan

4.2.1. Material and methods The Lahore data are from a follow-up study of the outcome of pregnancies registered in three areas, each with a population of 5000 (Jalil et al., 1993a; Hagekull et al., 1993). The areas represent different degrees of urbanisation in and near the city of Lahore: a typical village about 40 km from Lahore, a slum area at the periphery and a typical urban slum area in the city. The controls came from upper middle (UM) class families that lived in different locations in the city. Maternal illiteracy was common (93-95%) in the two poorer areas, i.e. the village and periurban slum, while it was only 51% in the urban slum. Eighty percent of the houses in the village and 95% in the periurban area were made of mud or straw, while the urban slum had 98% brick and 2% mud houses.

All pregnancies were registered over a period of 30 months, from September 1984 to March 1987. Of the 1476 children born alive, 159 died before reaching the age of 24 months, and 289 refused to participate in the study or moved from the area (Jalil et al., 1993a). Thus 1028 of the original cohort were in the study at the age of 24 months. In the present analysis all monthly observations were used. The growth of the upper middle class infants was used as reference for the other three groups for size, velocity and weight-for-length (Karlberg et al., 1993).

Information was collected on mortality, morbidity, body dimensions, teeth eruption, psychomotor development and feeding practices. The newborns were visited at home as soon as possible after birth, and subsequently every month during the first 24 months of life.

Some information is also included from a previous longitudinal study (1964-1978) of 910 infants living in a similar urban slum area in the center of Lahore (Karlberg, Jalil & Lindblad, 1988; Jalil et al., 1989).

4.2.2. Results and comments

Growth by area, sex and age. Fig. 6 gives the mean values of length for boys for each area in relation to the mean values in the NCHS reference (WHO Working Group, 1986; WHO, 1983). The mean length and weight of the UM class are close to the NCHS means, while the other three groups show various degrees of slower growth. Growth deficits are largest for the infants living in the periurban slum area, followed by those of the village. Weight and length for both sexes displayed similar patterns in relation to the NCHS reference as shown for length of the boys in Fig. 6.

The UM class-the reference group used in this work-was on the average 1.7 cm shorter than the NCHS reference mean at 24 months, so the proportion of infants characterised as being stunted in the other areas will be underreported from an international point of view. The incidence of reduced growth is shown in Fig. 7 by using the 3rd centile (approximately -2 SDS) of the NCHS reference at 24 months of age. In the two poorer areas about 75-83% of the infants were characterised as stunted at 24 months of age.

Growth in the two poorer areas by age. The boys and girls from the village and the periurban slum showed fairly similar mean growth values over the ages, and they were pooled in order to increase the sample size; their mean SDS values are given in Table 3. In Fig. 8 the smoothed mean SDS values are shown for weight, length and weight-for-length by age, and in Fig. 9 the proportion of the infants lying below -2 SDS for each measure. The stunting process starts at about 6 months of age and it continues to 18 months of age. At the same time the mean weight-for-length SDS increases from -1.0 and reaches the normal value of zero at 24 months of age. This faltering in length is similar to the findings in other similar areas around the world, although the proportion of the infants lying below -2 SDS in length in the two poorer areas at 24 months of age is one of the highest reported so far.

Fig. 6. Mean length of the Pakistani boys in the four study groups in relation to the NCHS reference - 3rd, 50th and 97th centiles (Karlberg et al., 1993).

Fig. 7. The incidence of stunting at 24 months of age for the Pakistani boys and girls in each of the four study areas based on the NCHS reference (Karlberg et al., 1993).

Table 3. Mean SDS values of different body measures (Lahore Study). Both sexes in the village and the periurban slum have been pooled. The proportions lying below -2 SDS are included for weight, length and weight for length (Karlberg et al., 1993)

		Attainted size						Delta SDS
		Weight (W)		Length (L)		W for L			Weight	Length
Age (mths)	n	mean SDS	%<-2 SDS	mean SDS	%<-2 SDS	mean SDS	%<-2 SDS	n	mean SDS	mean SDS
0	657	-0.84	9.3	0.79	11.4	-0.52	0.9
1	592	-1.09	16.4	-0.70	10.8	-0.87	6.1	516	-0.47	0.10
2	532	-1.13	18.2	-0.67	12.0	-0.94	12.6	432	-0.12	0.03
3	548	-1.14	19.9	-0.62	10.4	-0.98	14.8	420	0.00	0.10
4	523	-1.15	20.3	0.58	10.9	-1.02	16.1	407	-0.14	-0.03
5	528	-1.20	25.4	-0.74	15.5	-0.95	15.7	408	-0.11	-0.30
6	488	-1.29	27.5	-0.85	15.2	-0.98	15.2	393	-0.22	-0.36
7	472	-1.33	27.5	0.97	16.3	-0.93	15.5	354	-0.28	-0.55
8	470	-1.48	33.6	-1.22	22.3	-0.91	13.2	348	-0.34	-0.60
9	454	-1.64	35.7	-1.41	27.3	-0.96	15.6	343	-0.35	-0.54
10	454	-1.60	35.9	-1.51	31.1	-0.82	8.8	326	-0.19	-0.58
11	472	-1.66	36.7	-1.62	32.6	-0.80	9.3	346	-0.17	-0.47
12	474	-1.67	33.5	-1.73	37.3	-0.70	7.8	366	-0.01	-0.50
13	456	-1.69	35.5	-1.85	43.0	-0.62	6.8	343	0.17	-0.54
14	450	-1.67	35.1	-1.95	44.7	-0.51	4.0	341	0.13	-0.42
15	460	-1.66	35.2	-2.05	49.6	-0.41	3.0	345	0.14	-0.33
16	489	-1.57	35.0	-2.05	49.5	-0.31	2.5	360	0.19	-0.20
17	467	-1.56	33.2	-2.13	54.2	-0.19	1.5	375	-0.14	-0.26
18	452	-1.56	30.5	-2.16	57.3	-0.18	0.9	347	0.01	-0.06
19	466	-1.59	31.5	-2.20	55.6	-0.18	1.7	351	0.14	-0.07
20	459	-1.58	29.4	-2.22	56.4	-0.16	1.3	359	0.01	-0.01
21	462	-1.54	29.2	-2.25	57.1	-0.09	0.2	352	0.21	0.06
22	429	-1.46	27.0	-2.23	57.3	-0.02	0.7	331	0.17	0.15
23	429	-1.41	26.8	-2.22	56.2	-0.00	0.7	317	0.25	0.31
24	429	-1.35	22.4	-2.17	54.5	0.03	0.0	322	0.23	0.30

The monthly growth rate SDS values (standardised delta SDS values) are depicted in Fig. 10, using the mean values for weight and length as they are given in Table 3. Initially, these mean values are close to zero for the two measurements, i.e., they follow the path of the UM class. Mean delta SDS values for length are negative from 5 months of age, reach a minimum at 8-11 months, and become normal at 18 months. Weight is less affected than length in early life and reaches normal or close to normal monthly growth rate values at 12 months of age.

Growth in the two poorer areas by age and season. In Figs 11-12 the standardised delta SDS values (similar to velocity SDS values) of the monthly intervals are grouped according to age; the monthly intervals from birth to six months forming one group, and the monthly intervals from 6 to 12, 12 to 18 and 18 to 24 months constituting the other three groups (values not given in Tables). In Fig. 11 the mean length values are drawn for the four age groups over the months of the year. The monthly growth rates from birth to 6 months are close to the expected zero value with little seasonal variation. The growth rates from 6 to 12 months are also fairly constant over the seasons, but always reduced. During the second year of life, however, a marked seasonal variation in monthly growth rates is evident; the curves at 12-18 months and 18-24 months are similar in shape, but they are not at the same distance from the zero line of the reference group. Similar comparisons can be made for weight (Fig. 12), and the seasonal effect on weight gain, reaching its minimum during the summer, is evident in infants belonging to the four age groups.

Fig. 8. Mean SDS values for weight, length and weight-for-length over the ages. Both genders for the village and the periurban slum have been pooled (Table 3). The UM class group formed the reference population (Karlberg et al., 1993).

Many previous studies have demonstrated a significant seasonal influence on child growth in poor areas of developing countries: a reduced weight gain during the summer months and a reduced length gain a few months later (Martorell & Habicht, 1986; Jalil et al., 1989; Hauspie & Pagezy, 1989).

We can draw three conclusions from these results: (i) that the incidence of impaired growth was highly area-dependent; (ii) that the body measurement being most affected was length; and (iii) that the incidence of undernutrition (weight-for-length) was relatively low, especially from the second half of the first year of life onward. These results are very much in line with the results of other studies suggesting that body size reflects the general socio-economic standard of a population. However, this study shows in detail the substantial variation in growth among children from different socio-economic strata within the same city. The UM class mothers were on the average 156.3 cm in height, which is 10-11 cm below the mean height of European adult women (Eveleth & Tanner, 1976), but only 2-3 cm above the Pakistani mothers from the other, poorer areas (Jalil et al., 1993b). We are thus observing the rapid phase of a secular trend in the UM class.

Fig. 9. The proportion of the infants lying below -2 SDS for the different body measurements. Both genders for the village and the periurban slum have been pooled (Table 3). The UM class group formed the reference population.

Onset of the childhood phase. Fig. 13 pictures the individual longitudinal pattern of length in 21 randomly selected infants; 8 belonged to the UM class and 13 to the periurban slum. The two sets of data are close to each other in early life, but during the second part of the first year of life most of the infants belonging to the poor area show growth faltering. We have not yet analysed these data in terms of the age at onset of the childhood phase of growth. However, this has been done in a previous longitudinal study of infants from an urban slum area in Lahore (Karlberg, Jalil & Lindblad, 1988; Jalil et al., 1989).

Fig. 10. Mean standardised delta SDS (equal to velocity SDS) for the pooled sample of boys and girls in village and the periurban slum over the ages (Table 3). The UM class group formed the reference population (Karlberg et al., 1993).

The observed gain in length of children in the previous study was similar to that observed in the children from the two poorer areas of the ongoing Lahore study. Between birth and 24 months of age these children grew on average about 7.5 cm less in length than the NCHS reference. The deficit in length during the first two years of life was found to be highly related to the age at onset of the childhood component, but also to some extent to the housing standard, the parental education level and the sex of the child (Karlberg, Jalil & Lindblad, 1988).

The onset of the childhood component was on average, delayed by 5.5 months in comparison with normal Swedish children (Table 2), and 75% of the infants had a delayed onset, occurring after 12 months of age. In 14% the onset occurred very late, at 21-24 months of age. The impact of a late onset on length development is illustrated in Fig. 14. The two curves represent the mean length and mean growth rate values for the two groups of boys either having an estimated age at onset of 9 to 12 months or 18 to 21 months of age. There is an important difference in the two velocity curves from 9 to 18 months of age. At 21 months of age the mean difference in length between the two groups was 5.5 cm, or about 2 standard deviations. The shape of the curve for the group of boys with a late onset is continuously falling off from birth to 18 months with an exponential shape without any discontinuity. This empirical observation is intriguing, since it supports the idea of an exponential infancy phase of growth acting from birth till at least 18 months of age.

Fig. 11. Mean standardised length delta SDS (equal to velocity SDS) for the pooled sample of boys and girls in village and the periurban slum over the ages and months of the year (data not given in tables). The UM class group formed the reference population (Karlberg et al., 1993).

Three conclusions can be drawn here: (i) that the onset of the childhood phase of growth may be delayed in the majority of infants living in poor areas of developing countries, as observed in the Lahore study; (ii) that the age at onset is probably the key discriminator between normally growing infants and infants showing growth faltering in early life; and (iii) that the faltering curve probably represents a normal or close to normal extension of the infancy phase of growth, but the problem is that the childhood phase has not been initiated normally.

Fig. 12. Mean standardised weight delta SDS (equal to velocity SDS) for the pooled sample of boys and girls in village and the periurban slum over the ages and the months of the year (data not given in tables). The UM class group formed the reference population (Karlberg et al., 1993).

4.3. Observational studies of faltering - Hong Kong

The Hong Kong study is also a prospective longitudinal study of 371 infants followed from birth to 24 months of age (Zheng et al., 1989; 1991; Tam et al., 1990; Zheng, 1991; Lam et al., 1992). All children were born between November 1983 and December 1984 in the United Christian Hospital and lived under crowded conditions in a suburb located on the Kowloon Peninsula (Kwun Tong). The parents were young, seldom educated beyond primary school and belonged to low or lower middle income families.

The main objectives of the study were to study the incidence of diarrhoeal diseases and the causative pathogens; the effect of neonatal rotavirus infection on subsequent rotavirus infection, and their impact on weight gain. The results have been published elsewhere (Lam et al., 1992). During a total of 7808 infant months, there were a total of 329 diarrhoeal episodes of which 48.8% had positive isolates. Rotavirus gastroenteritis accounted for 14.7% (44 episodes) and bacterial gastroenteritis for 33.7% (102 episodes). The incidence of diarrhoeal disease was 0.8 episodes per child per year, which was considered to be a low figure.

Fig. 13. The individual length development in 8 upper middle class infants and 13 infants from the periurban slum in the Lahore study; selected by random.

In Hong Kong the child health care system has been developed during the past 40 years, and the care provided to the study group was optimal or close to optimal. Full immunisation was also provided to all infants in Hong Kong already at the time of the study. The infant mortality rate has declined in Hong Kong over the years and is now less than or equal to most European countries; 192.3/1000 in 1947,25.6 in 1967, 7.5 in 1987 and 4.7/1000 in 1992 (Infant mortality rate and neonatal mortality rate of Hong Kong, 1992). The feeding pattern is different in Hong Kong than in other parts of the world. Most mothers go back to work 1-2 months after delivery, so that virtually all infants are given formula, not breast milk, beyond 1-2 months of age.

Fig. 14. The mean length and mean growth rate values (mm/month) for two groups of Pakistani boys belonging to an urban slum area (Karlberg, Jalil & Lindblad, 1988). One group had an onset of the childhood phase of growth at 9-12 months of age and the other group at 18-21 months of age.

In the longitudinal study, infant development was monitored monthly by a clinician in one of the three community clinics in the suburb. Additional examinations were made at any sign of diarrhoeal disease. Weight was measured at each visit, length less frequently and in most infants at about 1, 7, 13 and 21 months of age (see Table 4).

Growth by sex and age. The data were initially treated cross-sectionally, i.e. month by month. Table 4 gives the mean values of weight and length by sex and age. Weight, but not length measurements were available for most infants from 1 to 24 months of age. Both weight and length were expressed in SDS using the NCHS growth reference values (WHO Working Group, 1986; WHO, 1983). The two sexes had similar mean SDS values for both weight and length over the ages and were consequently pooled. Fig. 15 gives the monthly mean weight SDS values. Also in this population we can note the faltering pattern, with normal weight values from 1 to 6 months of age, followed by a successive decrease in the values till 15 months of age. The vast majority of the infants were not breast-fed after 2 months of age, but the deficit in weight gain started only at 6 months of age.

Measures for both weight and length were selected for each child at 1,7,13 and 21 months of age. In cases where no examination had been made at these specific ages the nearest examination was selected (allowing for no more than 3 months' difference). Fig. 16 gives the proportion of the infants lying below -2 SDS from the mean of the NCHS reference for weight and length at 1, 7, 13 and 21 months. The percentage of infants thus being characterised as being short increased from a close to normal figure at 1 month to 12.3% at 21 months of age. The largest percentage increase occurred between 13 and 21 months. The shift in the whole distribution for length SDS is shown in Fig. 17; note that the percentage of the children that had a length above the reference mean decreased with age and reached a value of 25% at 21 months. The mean length SDS value decreased in a similar fashion over the ages and was -0.87 at 21 months of age. In spite of a low incidence of infectious disease in Hong Kong, the incidence of shortness at 21 months of age was quite high (12%).

An effort was made to determine the age at onset of the childhood phase in length in the Hong Kong infants. However, since length measurements were only taken infrequently in most of the infants, only the records of 19 infants could be used. In four of these cases (about 20%) we noted a delayed onset (after 12 months) of the childhood phase.

The Hong Kong infants show a much milder degree of growth faltering than the infants observed in the three poorer areas in Lahore. The faltering seems also here to be related to a delayed onset of the childhood phase of growth, and this in a population that was provided with good health care, a vaccination program and had a low incidence of disease.

5. Discussion

In this chapter we have discussed the three phases of linear growth in relation to the faltering process in length that is present in early life in most developing communities. The three phases of growth have been termed infancy, childhood and puberty, and they can be described mathematically in terms of the ICP growth model. Each of these three phases can be regarded in isolation, as being additive, and they are likely to represent three distinct endocrine phases.

Table 4. Weight and height of Hong Kong infants. Weight was taken at the monthly examinations in almost all infants, while length was measured at around 1, 7, 13 and 21 months of age in most of the infants. Mean and SD have been given for ages with 10 observations or more

Sex	Mean age (months)	Weight			Length
		n	Mean (kg)	SD (kg)	n	Mean (cm)	SD (cm)
Girls	1.2	153	4.15	0.39	153	53.5	2.00
	2.2	171	5.06	0.66	13	54.4	2.32
	3.2	165	5.77	0.71	0
	4.1	162	6.28	0.78	2
	5.1	166	6.80	0.76	0
	6.1	159	7.23	0.73	15	65.5	2.45
	7.1	159	7.46	0.76	80	66.5	2.67
	8.0	165	7.81	0.84	50	68.1	2.29
	9.1	166	8.08	0.90	16	68.7	2.24
	10.1	150	8.34	0.87	6
	11.0	155	8.44	0.87	4
	12.0	148	8.77	0.90	13	73.5	2.15
	13.0	144	9.00	0.90	29	74.5	2.76
	14.0	132	9.16	0.94	47	75.2	2.57
	15.0	126	9.36	0.97	25	76.0	2.87
	16.0	120	9.53	0.96	6
	17.0	126	9.77	0.97	11	78.8	2.83
	18.0	132	9.92	0.97	13	79.0	2.57
	19.0	86	10.16	1.05	8
	19.9	101	10.32	1.03	28	80.9	3.39
	21.0	100	10.36	1.15	27	80.6	3.41
	22.1	78	10.69	1.07	12	82.6	2.86
	23.0	72	10.98	1.12	8
	24.0	80	11.06	1.31	11	81.6	2.52
Boys	1.2	174	4.43	0.45	174	54.2	2.12
	2.2	186	5.58	0.74	8
	3.2	170	6.40	0.65	0
	4.1	169	6.96	0.73	1
	5.1	171	7.42	0.73	2
	6.0	180	7.85	0.78	23	67.3	2.41
	7.0	170	8.11	0.86	81	68.8	2.37
	8.0	163	8.49	0.89	55	69.1	2.48
	9.0	162	8.78	1.26	9
	10.0	164	8.87	0.93	4
	11.0	150	9.19	0.91	8
	12.0	155	9.40	0.97	16	73.7	2.33
	13.0	136	9.55	0.98	40	75.5	2.67
	14.0	139	9.80	0.99	39	77.7	2.84
	15.0	123	10.03	0.98	23	77.4	2.91
	16.0	128	10.28	1.08	15	78.6	2.92
	17.0	121	10.49	1.06	8
	18.0	120	10.70	1.11	13	81.5	3.36
	19.0	97	10.90	1.07	16	81.4	3.09
	20.0	106	11.13	1.19	29	83.1	2.96
	21.0	87	11.18	1.01	12	83.7	2.14
	22.0	99	11.45	1.12	16	83.2	3.35
	23.0	76	11.66	1.25	13	83.5	3.55
	24.0	86	11.74	1.21	11	85.0	2.15

Fig. 15. Mean weight SDS over the ages of Hong Kong infants based on the NCHS reference. Boys and girls are pooled.

Fig. 16. The incidence of stunting and low weight at different ages for the Hong Kong infants based on the NCHS reference. Both sexes are pooled and for each age and measure 180 to 220 observations were available.

Fig. 17. The distribution of length SDS at different ages based on the NCHS reference: the +0.5 SDS group, for instance, includes all infants with a length SDS of 0.0-0.99. Boys and girls are pooled.

The infancy phase is nutrition-dependent, the childhood phase GH-supported and the puberty portion driven by sex steroids, a hypothesis that is supported by current knowledge in endocrinology. One key point that is still very much debated is the time when GH starts to influence growth; some researchers believe that GH makes a major contribution to fetal growth, while others believe that it does not. In this chapter we have presented some empirical support for the view that GH may start to influence linear growth significantly at 6 to 12 months after birth, and that the onset of its action could very well correspond to the onset of the childhood phase of growth. Further research work is clearly needed to confirm this.

A delay in the onset of the childhood phase of growth seems to be the main determinant of the faltering in early growth. The reasons why the start of this phase is delayed in some children are still unclear. In normal Swedish infants, no relationship exists between the age at onset and season, feeding patterns, the age at which infants start walking, mid-parental height, or social group; only the growth rate prior to the age at onset is negatively related to the age at onset (Karlberg, 1989a; Karlberg et al., 1987a; Karlberg, Hägglund & Strömquist, 1991). In populations with a disturbed, or delayed onset, like the one in Lahore, we have not been successful in identifying any causal factors, when using information such as pattern of disease, feeding, or weight-for-length (unpublished observations). Further research is clearly needed in this area.

The incidence of faltering reflects socioeconomic standards, as shown in the Lahore study. These children lived in the same city and had the same ethnic background, but were brought up under very different conditions, from the privileged upper middle class group with good health care, housing standard and high parental education level to the very poor mud hut area in the periphery of the city with little or no health care provided and often illiterate parents. The upper middle class infants grew normally, without any clear signs of faltering, while the incidence of stunting reached 80% at 24 months of age in the poorer areas.

Clearly, environmental factors are a more likely cause of the stunting process than the ethnic or genetic background. Maternal illiteracy, poor hygiene, overcrowding, a high disease load and improper and/or contaminated food are all interacting in such environments. Whatever the causative factors are for the faltering process, they will remain if the general living conditions and educational level are not improved. Hong Kong has experienced a rapid socio-economic development during the last 40 years and is in many respects similar to Western European countries and North America. Despite this, some Hong Kong infants who are brought up under crowded conditions and belong to low or lower middle income families show growth faltering in early life, although to a much lesser degree than infants in poorer areas of developing countries. This suggests that it will take generations before the stunting problem has been eliminated, even in communities with fine financial resources and a well developed health care system.

Acknowledgements - This study was supported by grants from SAREC (the Swedish Agency for Research Collaboration with Developing Countries), the University of Hong Kong and the King Edward Medical College, Lahore, Pakistan.

References

Albertsson-Wikland K, Niklasson A & Karlberg P (1990): Birth data for patients who later develop growth hormone deficiency: preliminary analysis of a national register. Acta Paediatr. Scand, Suppl. 370, 115-120.

Barnard R, Haynes KM, Werther GA & Waters MJ (1988): The ontogeny of growth hormone receptors in the rabbit tibia. Endocrinology 122, 2562-2569.

Baron J, Oerter KE, Yanovski JA, Novosad JA, Bacher JD & Cutler GB (1993): Catch-up growth is intrinsic to the epiphyseal growth plate. Pediatr. Res., Suppl. 33, S41.

Black RE, Brown KH, Becker S & Yunus M (1982): Longitudinal studies of infectious diseases and physical growth of children in rural Bangladesh. I. Patterns of Morbidity. Am. J. Epidemiol. 155, 305-314.

Cianfarani S & Holly JMP (1989): Somatomedin - binding proteins: what role do they play in the growth process? Eur. J. Paediatr. 149, 76-79.

Copeland KC, Paunier L & Sizonenko PC (1977): The secretion of adrenal androgens and growth patterns of patients with hypogonadotropic hypogonadism and idiopathic delayed puberty. J. Pediatr. 91, 985-990.

Costello AM (1989): Growth velocity and stunting in rural Nepal. Arch. Dis. Child. 64, 1478-1482.

Dean HJ, Schentag CT & Winter JS (1990): Predictive values of short-term growth using knemometry in a large population of healthy children. Acta Paediatr. Scand. 79, 57-63.

Degan R, Sofor S, Klish WJ et al. (1983): Growth and nutritional status of Bedouin infants in Negev Desert, Israel: evidence for marked stunting in the presence of only mild malnutrition. Am. J. Clin. Nutr. 38, 747-756.

Dewey KG, Peerson JM, Heining MJ et al. (1992): Growth patterns of breast-fed infants in affluent (United States) and poor (Peru) communities: implications for timing of complementary feeding. Am. J. Clin. Nutr. 56, 1012-1018.

Eveleth PB & Tanner JM (1976): Worldwide variation in human growth. Cambridge: University Press.

Frasier SD (1983): Human pituitary growth hormone (hGH) therapy in growth hormone deficiency. Endocr. Res. 4, 155-170.

Gluckman PD (1989): Fetal growth: an endocrine perspective. Acta Paediatr. Scand., Suppl. 349, 21-25.

Gluckman PD, Gunn AJ, Wray A et al. (1992): Congenital idiopathic growth hormone deficiency associated with prenatal and early postnatal growth failure. J. Pediatr. 121, 920-923.

Hagekull B, Nazir R, Jalil F & Karlberg J, (1993): Early child health in Lahore, Pakistan. III. Maternal and family situation. Acta Paediatr. Scand, Suppl. 390, 27-37.

Hauspie RC & Pagezy H (1989): Longitudinal study of growth of African babies: An analysis of seasonal variations in the average growth rate and the effects of infectious diseases on individual and average growth patterns. Acta Paediatr. Scand., Suppl. 350, 37-43.

Hermanussen M, Geiger-Benoit K, Burmeister J & Sippell WG (1988): Knemometry in childhood: accuracy and standardization of a new technique of lower leg length measurement. Ann. Hum. Biol. 15, 1-16.

Hill DJ (1989): Cell multiplication and differentiation. Acta Paediatr. Scand, Suppl. 349, 13-20.

Hill DJ, Freemark M Strain AJ, Handwergers S & Milner RDG (1988): Placental lactogen and growth hormone receptors in human fetal tissues: relationship to fetal human placental lactogen concentrations and fetal growth. J. Clin. Endocrinol. Metab. 66, 1283-1290.

Infant mortality rate and neonatal mortality rate of Hong Kong (1946-1992) (1992): Annual departmental report by Director of Medical and Health Services. The Government of Hong Kong 1992.

Jalil F, Karlberg J, Hanson LÅ & Lindblad BS (1989): Growth disturbances in an urban area of Lahore, Pakistan related to feeding patterns, infections and age, sex, socioeconomic factors and seasons. Acta Paediatr. Scand., Suppl. 350, 44-54.

Jalil F, Lindblad BS, Hanson LÅ et al. (1993a): Early child health in Lahore, Pakistan. I. Study design. Acta Paediatr. Scand., Suppl. 390, 3-16.

Jalil F, Lindblad BS, Hanson LÅ, Khan SR, Yaqoob M & Karlberg J (1993b): Early child health in Lahore, Pakistan. IX. Perinatal events. Acta Paediatr., Suppl. 390, 95-107.

Karlberg J (1987): On the modelling of human growth. Stat. Med. 6, 185-192.

Karlberg J (1989a): A biologically-oriented mathematical model (ICP) for human growth. Acta Paediatr. Scand., Suppl. 350, 70-94.

Karlberg J (1989b): On the construction of the infancy-childhood-puberty growth standard. Acta Paediatr. Scand, Suppl. 356, 26-37.

Karlberg J (1990): The infancy-childhood growth spurt. Acta Paediatr. Scand, Suppl. 367, 111-118.

Karlberg J & Wit JM (1991): Linear growth in Sotos syndrome. Acta Paediatr. Scand 80, 956-957.

Karlberg J & Albertsson-Wikland K (1988): Infancy growth pattern related to growth hormone deficiency. Acta Paediatr. Scand. 77, 385-391.

Karlberg J, Jalil F & Lindblad BS (1988): Longitudinal analysis of infantile growth in an urban area of Lahore, Pakistan. Acta Paediatr. Scand. 77, 392-401.

Karlberg J, Albertsson-Wikland K & Naeraa RW (1991): The infancy-childhood-puberty (ICP) model of growth for Turner girls. In Turner syndrome: Growth promoting therapies, eds MB Ranke & RG Rosenfeldt, pp. 89-94. Elsevier Science Publishers.

Karlberg J, Hägglund G & Strömquist, B (1991): Immobilization related to early linear growth. Acta Paediatr. Scand 80, 833-836.

Karlberg J, Kjellmer I & Kristiansson B (1991): Linear growth in children with Cystic Fibrosis. I. Birth to eight years of age. Acta Paediatr. Scand 80, 508-514.

Karlberg J, Engström I, Karlberg P & Fryer JG (1987a): Analysis of linear growth using a mathematical model. I. From birth to three years. Acta Paediatr. Scand. 76, 478-488.

Karlberg J, Fryer JG, Engström I & Karlberg P (1987b): Analysis of linear growth using a mathematical model. II. From 3 to 21 years of age. Acta Paediatr. Scand, Suppl. 337, 12-29.

Karlberg J, Henter J-I, Tassin E & Lindblad BS (1988): Longitudinal analysis of infantile growth in children with celiac disease. Acta Paediatr. Scand. 77, 516-524.

Karlberg J, Albertsson-Wikland K, Nilsson KO, Ritzén EM & Westphal O (1991): Growth in infancy and childhood in girls with Turner's syndrome. Acta Paediatr. Scand. 80, 1158-1165.

Karlberg J, Ashraf RN, Saleemi M, Yaqoob M & Jalil F (1993): Early child health in Lahore, Pakistan. XI. Growth. Acta Paediatr. Scand., Suppl. 390, 119-149.

Keenan BS, Richards GE, Ponder SW, Dallas JS, Nagamani M & Smith ER (1993): Androgen-stimulated pubertal growth: the effects of testosterone and dihydrotestosterone on growth and insulin - like growth factor - I in the treatment of short stature and delayed puberty. J. Clin. Endocrinol. Metab. 76, 996-1001.

Lam BCC, Tam J, Ng MH, Yeung CY & Lo M (1992): The protective role of neonatal rotavirus infection: A prospective longitudinal study. Hong Kong J. Paediatr. 9, 166-171.

Lampl M, Veldhuis JD & Johnson ML (1992): Saltation and stasis: a model of human growth. Science 258, 801-803.

Manwani AH & Agarwal KN (1973): The growth pattern of Indian infants during the first year of life. Hum. Biol. 45, 341-349.

Martorell R & Habicht JP (1986): Growth in early childhood in developing countries. In Human growth, vol. 3, 2nd edn, eds F Falkner & JM Tanner, pp. 241-262. New York: Plenum Press.

Massa G, de Zegter F & Vanderschueren-Lodeweyckx M (1992): Serum growth hormone-binding proteins in the human fetus and infant. Pediatr. Res. 32, 69-72.

Mata LJ (1978): The children of Santa Maria Cauqué: A prospective field study of health and growth. Massachusetts: The MIT Press.

Michaelson KF, Skov L, Badsberg JH & Jorgensen M (1991): Short-term measurement of linear growth in pre-term infants. Validation of a hand-held knemometer. Pediatr. Res. 30, 464-468.

Milner RDG & Hill DJ (1987): Interaction between endocrine and paracrine peptides in prenatal growth control. J. Pediatr. 146, 113-132.

Oerter KE, Bacher JD, Cutler GB & Baron J (1993): Linear growth in the rabbit is continuous, not saltatory. Pediatr. Res., Suppl. 33, S41.

Pescovitz OH (1990): The endocrinology of the pubertal growth spurt. Acta Paediatr. Scand., Suppl. 367, 119-125.

Smith DW (1977): Growth and its disorders (Major problems in clinical pediatrics, vol. 15). Philadelphia, PA: W.B. Saunders Company.

Stanhope R, Pringle PJ & Brook CGD (1988): The mechanism of the adolescent growth spurt induced by low dose pulsatile GnRH treatment. Clin. Endocrinol. 28, 83-91.

Tam JSL, Zheng BJ, Yeung CY et al. (1990): Distinct populations of rotaviruses circulating among neonates and older infants. J. Clin. Microbiol. 28, 1033-1038.

Tse WY, Hindmarsh PC & Brook CGD (1989): The infancy-childhood-puberty model of growth: Clinical aspects. Acta Paediatr. Scand, Suppl. 356, 38-43.

Valk I, Langhout Chabloz A, Smaals AGH, Kloppenborg PWC, Cassorla FG & Schutte EAST (1983): Accurate measurements of the lower leg length and the ulnar length and its application in short term growth measurement. Growth 47, 53-66.

Wales JK & Milner RDG (1987): Knemometry in assessment of linear growth. Arch. Dis. Child 62, 166-171.

Waterlow JC, Ashworth A & Griffiths M (1980): Faltering in infant growth in less-developed countries. Lancet 2, 1176-1178.

Waters MJ, Barnard RT, Lobie PE et al. (1990): Growth hormone receptors - their structure, location and role. Acta Paediatr. Scand, Suppl. 366, 60-72.

Westher GA, Haynes KM & Waters MJ (1991): Growth hormone (GH) receptors are present in human fetal tissues. Proceedings of the 73rd Annual Hormonal Meeting, p. 418. Washington DC: The Endocrine Society.

WHO (1983): Measuring change in nutritional status: guidelines for assessing the nutritional impact of supplementary feeding programmes for vulnerable groups. Geneva: World Health Organization.

WHO Working Group (1986): Use and interpretation of anthropometric indicators of nutritional status. Bull. WHO 64, 929-941.

Wit JM, Teunissen DM, Waelkens JJJ & Grever WJ (1987): Comparison of short-term lower leg growth with statural growth in children treated with growth promoting substances. Acta Paediatr. Scand, Suppl. 337, 40-43.

Zheng BJ, Lo SKF, Tam JS et al. (1989): Prospective study of community-acquired rotavirus infection. J. Clin. Microbiol. 27, 2083-2090.

Zheng BJ, Tm SL, Lam BCC et al. (1991): The effect of maternal antibodies on neonatal rotavirus infection. J. Paediatr. Infect. Dis. 10, 865-868.

Zumrawi FY, Dimond H & Waterlow JC (1987): Faltering in infant growth in Karthoum province, Sudan. Hum. Nutr.: Clin. Nutr. 41, 383-395.

Discussion

There is still room for discussion about the natural history of stunting. In the Pakistan study there was some fall-off in linear growth even during the 'infancy' phase. This may be related, at least in part, to size at birth (see discussion of paper by Falkner). Deaths during the first month were related to length at birth. The general opinion was that, in this early phase, the problem was not one of nutritional deficiency. In Pakistan, during the first 6 months, only 15% of children had a seriously low weight-for-length (below -2 SD). Therefore it does not seem likely that the deficit in linear growth was a consequence of failure to gain weight. Similarly, in Chile young children get all the food they need and become overweight for length, but still lag behind in linear growth (Uauy).

It seems probable that infections have something to do with early growth retardation. Breast-fed children without diarrhoea gained 1.5 cm more than those who were not breast-fed and did have diarrhoea. Even in the absence of diarrhoea there was a small difference (about 0.5 cm) between children who were or were not breast-fed. Moreover, it must be remembered that there are other benefits from breast-feeding, in addition to the prevention of infection; it provides a special type of emotional bonding, which is very important for the child's growth (see paper by Skuse). Breast-feeding, however, did not give total protection against stunting because these children also received water, and water carries pathogens.

In any case, the main problem is the growth retardation that becomes much more serious after 6 months. In the Pakistan sample, only 3% had a deficit in linear growth between birth and 6 months, compared with 31% between 6 and 20 months. This is the time when weaning foods are being introduced and infections become more frequent. According to one opinion, this could be an adequate explanation of the falling off in growth and there is nothing more to be said (Neumann). Others, however, preferred to dig more deeply. The hypothesis proposed is that there is a lag in the onset of the childhood phase of growth, but what causes this lag? Karlberg's data showed that the children who faltered in the first 6 months were not necessarily those whose growth was most retarded later on. Growth in these two phases appeared to be independent. The correlation between growth velocity at 1 month and at 1 year was only about 0.6. Thus, though short-term changes may be useful for exploring mechanisms, they cannot provide projections.

There followed a discussion of hormonal responses, which may well be mediated by nutritional factors such as amino acids or minerals (see paper by Allen). No measurements of growth hormone were made in the Pakistan study' because it was not considered ethical to take the large number of blood samples needed to give a profile of GH secretion over 24 hours; in the future it may be possible to overcome this difficulty by urine assays - a possibility that is being explored at INCAP (Torun). It is well established that early in severe PEM, GH levels are increased. The hypothesis is that GH fails to stimulate growth in the childhood phase because of a defect in the receptors. One way of investigating this would be to see if there is any change in the amounts of receptor mRNA, but this has not yet been done (Nilsson). Another possibility is that there is no change in receptors, but a reduced production of IGF-1, so that the defect would be at the post-growth hormone receptor level. On either hypothesis, the defect would only appear when growth hormone enters the picture, at about 6 months. One example is coeliac disease; infants with this condition grow perfectly normally from birth to 6 months, but then they do not start the second phase of growth until they have been treated. If they are treated properly, growth resumes after 1-1½ months (Karlberg). But the question remains: what is holding up entry into the second phase? Even if we accept that the lag results from chronic malnutrition and/or infection, what is the mechanism? This remains a question for the future.